title: Mutations in PIK3R1 cause SHORT syndrome.
abstract: SHORT syndrome is a rare, multisystem disease characterized by short stature, anterior-chamber eye anomalies, characteristic facial features, lipodystrophy, hernias, hyperextensibility, and delayed dentition. As part of the FORGE (Finding of Rare Disease Genes) Canada Consortium, we studied individuals with clinical features of SHORT syndrome to identify the genetic etiology of this rare disease. Whole-exome sequencing in a family trio of an affected child and unaffected parents identified a de novo frameshift insertion, c.1906_1907insC (p.Asn636Thrfs*18), in exon 14 of PIK3R1. Heterozygous mutations in exon 14 of PIK3R1 were subsequently identified by Sanger sequencing in three additional affected individuals and two affected family members. One of these mutations, c.1945C>T (p.Arg649Trp), was confirmed to be a de novo mutation in one affected individual and was also identified and shown to segregate with the phenotype in an unrelated family. The other mutation, a de novo truncating mutation (c.1971T>G [p.Tyr657*]), was identified in another affected individual. PIK3R1 is involved in the phosphatidylinositol 3 kinase (PI3K) signaling cascade and, as such, plays an important role in cell growth, proliferation, and survival. Functional studies on lymphoblastoid cells with the PIK3R1 c.1906_1907insC mutation showed decreased phosphorylation of the downstream S6 target of the PI3K-AKT-mTOR pathway. Our findings show that PIK3R1 mutations are the major cause of SHORT syndrome and suggest that the molecular mechanism of disease might involve downregulation of the PI3K-AKT-mTOR pathway.
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada. ddyment@cheo.on.ca
authors.forename: David A
authors.initials: DA
authors.lastname: Dyment
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Smith
authors.forename: Diana
authors.initials: D
authors.lastname: Alcantara
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Schwartzentruber
authors.forename: Lina
authors.initials: L
authors.lastname: Basel-Vanagaite
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Curry
authors.forename: I Karen
authors.initials: IK
authors.lastname: Temple
authors.forename: William
authors.initials: W
authors.lastname: Reardon
authors.forename: Sahar
authors.initials: S
authors.lastname: Mansour
authors.forename: Mushfequr R
authors.initials: MR
authors.lastname: Haq
authors.forename: Rodney
authors.initials: R
authors.lastname: Gilbert
authors.forename: Ordan J
authors.initials: OJ
authors.lastname: Lehmann
authors.forename: Megan R
authors.initials: MR
authors.lastname: Vanstone
authors.forename: Chandree L
authors.initials: CL
authors.lastname: Beaulieu
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Bulman
authors.forename: Mark
authors.initials: M
authors.lastname: O'Driscoll
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D059472:Exome; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D006580:Genetic Carrier Screening; D006130:Growth Disorders / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D006934:Hypercalcemia / Q000235:genetics*; D007231:Infant, Newborn; D008297:Male; D008659:Metabolic Diseases / Q000235:genetics*; D009397:Nephrocalcinosis / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D058543:Class Ia Phosphatidylinositol 3-Kinase